This is the U.S. national phase of International Application No. PCT/EP99/02386 filed Apr. 8, 1999, the entire disclosure of which is incorporated herein by reference.
1. Field of the Invention
The present invention relates to slow-release tablets comprising linear water-insoluble polysaccharides, a process for preparation, and use thereof, in particular for the controlled release of active compounds.
2. Description of Related Technology
In modern pharmaceutical technology, formulations of excipients whose administration form specifically brings an influence to bear on the biodistribution, bioavailability, biocompatibility and absorption are of importance. Moreover, excipients must have good mechanical properties, such as adequate hardness and resistance to tension and stress. Although a few compounds can already be pressed themselves to give compact stable masses (e.g. sucrose or lactose), ingredientsxe2x80x94tablet auxiliariesxe2x80x94are also necessary, such as binders, fillers, lubricants and additives. Typical dry binders for increasing stability which are used here are:
calcium phosphates, microcrystalline cellulose (e.g. Avicel(copyright), PH 102(copyright), especially Celsphere), polyvinylpyrrolidones (e.g. Kollidon(copyright), Luviskol VA 64(copyright), Plasdone(copyright)), corn, wheat or potato starch, derivatized polysaccharides, so-called gums, (e.g. xanthan gum), cellulose derivatives (e.g. hydroxypropylmethylcellulose: Klucel(copyright)) or ethylcellulose (Aqualon(copyright)). Moreover, the excipients must disintegrate in the body in an optimum and controlled manner in contact with body fluids. Therefore, so-called disintegrants are often added for disintegration control. Typical compounds for this purpose are corn starch, gelatinized starch and starch modifications. Substances which can also be employed are those which develop a disintegrating power due to water absorption and accompanying swelling. These include crosslinked polyvinylpyrrolidones (Kollidon CL(copyright)), carboxymethylcellulose and their calcium salts or galactomannans. With some compounds (e.g. Avicel(copyright) and PH 102(copyright)), it is possible to achieve both the necessary mechanical stability and to control tablet disintegration.
Specific starches, including amylose, are described as advantageous excipients for tablet formulation (Journal of Pharmaceutical Sciences 55 (1966), 340). However, the Nepol amylose used (A. E. Stanley Manufacturing Co., USA) proves disadvantageous, since the active compounds are not exhaustively released and the excipient has a high water content (10-12%), which is why hydrolytically labile active compounds cannot be formulated. In particular, crosslinked amylose (degree of crosslinkage 15%) is as a superior binding agent described (S.T.P. Pharma Sciences 4 (1994), 329-335 and Journal of Controlled Release 15, (1991) 39-46, Journal of Controlled Release 15, (1991) 3946), which on account of its water absorption capacity acts as a disintegration accelerator. In WO 94/21236, crosslinked amylose (degree of crosslinkage 25%) is used as a binder and disintegrant. A high degree of crosslinkage, however, has a disadvantageous effect on the biological compatibility. The crosslinking agent used is up to 30% by weight of the intolerable epichlorohydrin. Even low crosslinkages in the range of a few percent lead to a rapidly growing slowness to react, so residues of unreacted crosslinker which remain have to be expected.
All starch- and amylose-containing excipients on the market until now use plant sources of origin.
It is disadvantageous here that these biopolymers, like all naturally occurring substances, have considerable variations in composition and structure and therefore the necessary reproducibility and thus constant product quality is not guaranteed, even with respect to controlled release of active compound.
In the case of native starch, the content of amylose and amylopectin varies considerably depending on the origin. For example, starch from potatoes contains about 20% by weight of amylose and about 80% by weight of amylopectin, whereas starch from corn contains about 50% by weight of amylose and about 50% by weight of amylopectin. Additional variance within a plant community results due to soil condition, fertilizer absorption, seasonal climatic differences etc.
Moreover, amylose, a 1,4-linked polyglucan, having a molecular weight of approximately 50,000 to 150,000 daltons, and amylopectin, a highly branched 1,4- and 1,6-linked polyglucan, having a molecular weight of approximately 300,000 to 2,000,000 daltons, have wide molecular weight distributions.
The transitions from highly branched to linear are fluid and vary in the original plant material, so that a sharp delimitation is almost impossible. In particular, excipients which still contain amylopectin cause irregular swelling on account of the branchings, whereby the carrier stability is adversely affected. Amylopectin is therefore usually laboriously removed by means of enzymatic debranching (Journal of Controlled Release 45, (1997) 25-33 and EP 0499 648 B1=U.S. Pat. No. 5,468,286).
Beside these marked disadvantages, the wide molecular weight distribution or mixtures of polymers of different spatial arrangements, native polymers contain further constituents such as low molecular weight compounds, e.g. fats and oils, which can only be separated with difficulty and have a disadvantageous effect in further processing and application (e.g. U.S. Pat. No. 3,490,742). In particular, yield-decreasing working steps have to be carried out, in some cases it not being possible to eliminate impurities completely.
Experiments are also known to optimize biopolymers, i.e. even starch, by genetically modifying the plant of origin. WO 94/03049 describes the preparation and use of high amylose-containing starch from genetically modified corn. Regardless thereof, the disadvantages of nonuniformity and contamination remain.
The reproducibility and quality is substantially dependent on the uniformity and purity. To guarantee products of high quality, these starting substances must be clearly definable and characterizable.
The present invention has the object, while avoiding the above disadvantages, of making available a slow-release material which can be used as a slow-release tablet in a pharmaceutical composition for the controlled release of active compounds, preferably for oral administration.
The object is achieved by using as the slow-release material water-insoluble linear polysaccharides which are biocompatible, chemically inert, pressure-stable starting materials which make possible the controlled release of active compound without further additives. Preferably, the starting material used is linear water-insoluble poly(1,4-alpha-D-glucan) as such or in the form of spherical microparticles.
xe2x80x9cSlow-release tabletsxe2x80x9d in the sense of the present invention are, in particular, tablets, coated tablets, pills, pellets, pressings, small plates, disks and the like, whose formulation requires compression. Likewise to be included are capsules which are filled with the slow-release material.
Slow-release materials are to be regarded in the following as linear water-insoluble polysaccharides.
Linear water-insoluble polysaccharides in the sense of the present invention are polysaccharides, preferably polyglucans, in particular poly(1,4-alpha-D-glucan), which consist of monosaccharides, disaccharides, further oligomers thereof or derivatives.
These are always linked to one another in the same way. Each base unit defined in this way has exactly two linkages, each one to another monomer. Excluded therefrom are the two base units, which form the beginning and end of the polysaccharide. These base units have only one linkage to a further monomer. In the case of three or four linkages (covalent bonds) of a monomer to another group, preferably a further saccharide unit, branching is referred to. At least three glycosidic bonds then leave from each saccharide unit in the polymer backbone.
According to the invention, branchings do not occur or only occur to such an insignificant extent that, in the very small branching proportions present, in general they are no longer accessible to the conventional analytical methods. This is the case, for example, when based on the totality of all hydroxyl groups present to one hundred hydroxyl groups which are not needed for the synthesis of the linear polysaccharide, at most five hydroxyl groups are taken by linkages to other saccharide units.
The degree of branching here is maximal (100%) if, on each saccharide unit, the free hydroxyl groups (or other functional groups occurring) have further glycosidic (or other) bonds to further saccharides. The degree of branching is minimal (0%) if, in the saccharides, apart from the hydroxyl groups which determine the linearity of the polymer, no further hydroxyl groups are modified by chemical reaction.
Examples of preferred water-insoluble linear polysaccharides are linear poly-D-glucans, where the type of linkage is insignificant as long as linearity in the sense of the invention is present. Examples are poly(1,4-alpha-D-glucan) and poly(1,3-beta-D-glucan), poly(1,4-alpha-D-glucan) being particularly preferred.
If the base unit has three or more linkages, this is referred to as branching. The so-called degree of branching results here from the number of hydroxyl groups per 100 base units which are not involved in the synthesis of the linear polymer backbone and which form branchings.
According to the invention, the linear water-insoluble polysaccharides have a degree of branching of less than 8%, i.e. they have less than 8 branchings to 100 base units. Preferably, the degree of branching is less than 4% and in particular at most 1.5%.
If the water-insoluble linear polysaccharide is a polyglucan, e.g. poly(1,4-alpha-D-glucan), the degree of branching in the 6-position is less than 4%, preferably at most 2% and in particular at most 0.5%, and the degree of branching in the other positions not involved in the linear linkage, e.g. the 2- or 3-position in the case of the preferred poly(1,4-alpha-D-glucan), is preferably in each case at most 2% and in particular at most 1%. Particularly preferred are polysaccharides, in particular poly-alpha-D-glucans, which have no branchings, or whose degree of branching is so minimal that it is no longer detectable using conventional methods.
According to the invention, the prefixes xe2x80x9calphaxe2x80x9d, xe2x80x9cbetaxe2x80x9d or xe2x80x9cDxe2x80x9d on their own relate to the linkages which form the polymer backbone and not to the branchings.
xe2x80x9cwater insolubilityxe2x80x9d in the sense of the present invention means that no detectable solubility of the compound exists under normal conditions (room temperature of 25xc2x0 C. and an air pressure of 101325 pascals or based on values differing at most 20% therefrom).
In the case of the polysaccharides used according to the invention, in particular of the polyglucans such as poly(1,4-alpha-D-glucan), this means that at least 98% of the amount employed, preferably an amount of greater than 99.5%, is insoluble in water. The term insolubility here can also be explained with the aid of the following observation. If 1 g of the linear polysaccharide to be investigated is heated to 130xc2x0 C. in 1 I of deionized water under a pressure of 1 bar, the resulting solution only remains stable briefly, for a few minutes. On cooling under normal conditions, the substance reprecipitates. After a further cooling and separation using the centrifuge with inclusion of experimental losses, at least 66% of the amount employed can be recovered in this way.
In the context of this invention, linear, water-insoluble polysaccharides are preferably used which can be obtained with the aid of generally defined biotechnological or genetic engineering methods. A particularly advantageous embodiment of the invention described here is the preparation in a biotechnological process, in particular in a biocatalytic process.
Linear polysaccharides prepared by biocatalysis (also: biotransformation) in the context of this invention means that the linear polysaccharide is prepared by catalytic reaction of monomeric base units such as oligomeric saccharides, e.g. of mono- and/or disaccharides, by using a so-called biocatalyst, customarily an enzyme, under suitable conditions. Preferably, poly(1,4-alpha-D-glucan) in particular is prepared by means of polysaccharide syntheses and/or starch synthases and/or glycosyl transferases and/or alpha-1,4-glucan transferases and/or glycogen synthases and/or amylosucrases and/or phosphorylases.
Likewise conceivable are linear polysaccharides from fermentation. In the context of this invention, these are linear polysaccharides which can be obtained by enzymatic processes using naturally occurring organisms, such as fungi, algae or microorganisms or using organisms not occurring naturally, which can be obtained by modification of natural organisms, such as fungi, algae or microorganisms, by means of generally defined genetic engineering methods.
Moreover, linear polysaccharides can be obtained for the preparation of the slow-release tablet described in the present invention from nonlinear polysaccharides which contain branchings by treating them with an enzyme and linear polymers thereof can be obtained with cleavage (e.g. by means of enzymes, such as amylase, isoamylase, gluconohydrolase, pullulanase, inter alia) and removal of the branchings.
The molecular weights Mw of the linear polysaccharides used according to the invention can vary in a wide range from 103 g/mol to 107 g/mol, the molecular weights Mw preferably lie in the range from 2xc3x97103 g/mol to 5xc3x97104 g/mol, in particular 3xc3x97103 g/mol to 2xc3x97104 g/mol. For the linear polysaccharide poly(1,4-alpha-D-glucan) preferably used, corresponding ranges are used.
The molecular weight distribution or polydispersity Mw/Mn can vary within wide ranges depending on the method of preparation of the polysaccharide. A polydispersity of 1.01 to 50 is preferably employed, particularly preferably from 1.5 to 15. In this case, the polydispersity increases with a bimodal distribution of the molecular weights, this not adversely affecting the properties of the tablet formulation.
Mixtures of linear polysaccharides according to the invention and in the form of microparticles with nonlinear polysaccharides are not excluded. xe2x80x9cControlled release of active compoundxe2x80x9d is understood as meaning that the active compound is released after a certain time and/or period of time in a dose advantageous for the biological organism with acceptance of a statistical deviation corresponding to the circumstances.
This definition also includes extremes. On the one hand, the spontaneous release of all active compounds present in the formulation within a period of time approximating to the value zero, on the other hand, the minimal necessary amount dose for the attainment of a therapeutic effect over a long, even infinite period of time, at least a period of time which is necessary to release all active compounds present in the formulation.
For the slow-release formulation present here, therefore, reference is synonymously made to a depot formulation or formulation having delayed release. An xe2x80x9cactive compoundxe2x80x9d is regarded as any biologically active substance and substance combination in the widest sense (specifically in the human and veterinary area), in particular for medicinal indication. In particular: analgesics, anginal preparations, antiallergics, antihistamines, antiinflammatories, bronchodilators, bronchospasmolytics, diuretics, anticholinergics, antiadhesion molecules, cytokine modulators, biologically active endonucleases, recombinant human DNases, neurotransmitters, leukotriene inhibitors, vasoactive intestinal peptides, endothelin antagonists, analeptics, local anesthetics, anesthetics, antiepileptics, anticonvulsants, antiparkinson agents, antiemetics, compounds regulating or stimulating the hormone system, compounds regulating or stimulating the cardiovascular system, compounds regulating or stimulating the respiratory tract system, vitamins, trace elements, antioxidants, cytostatics, antimetabolites, antiinfectives, immunomodulators, immunosuppressants, antibiotics, proteins, peptides, hormones, growth hormones, growth factors, xanthines, vaccines, steroids and beta2-mimetics.
xe2x80x9cTherapeutic effectxe2x80x9d in the sense of this invention means that a therapeutically effective amount of an active compound reaches the desired target site, displays its action there, and causes a physiological reaction. The palliative and/or curative effect is included.
xe2x80x9cBiocompatiblexe2x80x9d in the sense of this invention means that the polysaccharides employed are subjected to complete biodegradation and no concentration in the body takes place. Biodegradation here is understood as meaning any process taking place in vivo which leads to a degradation or destruction of the polymer. In particular, hydrolytic or enzymatic processes are likewise included in this area. For the biocompatibility of the polysaccharides and of its degradation products (metabolites), not least is the naturally identical character of the polysaccharides employed of high importance. Therefore, the polysaccharides used according to the invention are suitable for therapeutic, diagnostic or prophylactic use. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d in the sense of this invention means that a vehicle for an active compound, an auxiliary or alternatively so-called excipient, can be absorbed by a living being without significant side effects arising for the organism.
The tablets are prepared by mixing the starting components, the linear polysaccharide being mixed or homogenized together with the active compound according to known methods, e.g. with the aid of a ball mill. The active compound can have a concentration of up to 50%, a concentration between 1 and 20%, particularly preferably between 5 and 15%, preferably being used. Further customary auxiliaries and additives can be employed. The sum of active compound and polysaccharide according to the invention in the total composition (including possible auxiliaries and additives) should be at least 50%, however 70 to 100% is preferred and 85 to 98% is particularly preferred. The composition of the auxiliaries can vary within wide ranges, the ratios of the composition depending on the interactions with the active compound and the linear water-insoluble polysaccharide.
Auxiliaries which can be employed in tablet production and in the preinserted mixing process are solvents, readily volatile solvents being preferred.
The parent structure of the polysaccharide according to the invention for tablet production can be an amorphous or crystalline structure or grain, such as is obtained directly in synthesis, or alternatively a microparticle, such as is described by the patent application (German Patent Office, ref.: 197 37 481.6). The simple mixing process is preferably used for the preparation of the raw material or raw mixture of the tablet. This preparation procedure of the tablets can affect the properties of the tablet. For example, it is possible to couple the active compound directly on or to the parent structure of the polysaccharide by spraying techniques, for example in the fluidized bed process or by coating in a suspension of the polysaccharide used according to the invention. Absorption processes can be employed here, in which the porous structure of the microparticles is utilized in order to absorb the active compound in a solution (sponge character), or spray-drying techniques. Here, a solution, suspension or emulsion of a linear polysaccharide and of the active compound is dried by means of known spray technologies. In the case of solutions, corresponding organic solvents are employed. Higher temperatures or pressures, and supercritical processes can help to produce the necessary solubilities for short periods of time.
The pressures used during tablet production can vary within wide ranges. Pressure variations can be specifically employed with the polysaccharides described according to the invention to achieve an additionally positively acting slow-release effect. The pressures can vary within wide ranges from 1 MPa to 103 MPa. (105 Pa=1 bar). Pressures in the range from 10 MPa to 300 MPa are preferably to be employed, particularly advantageously pressures in the range from 100 MPa to 250 MPa.